Hemoproteins are a group of proteins which contain a heme prosthetic group. They include cytochromes and hemoglobins. These proteins play a critical role in the bioenergetics of aerobic metabolism in mammals, and individuals with mutations or deficiencies in these proteins can have deficiencies in oxygen delivery (e.g., sickle cell anemia) and electron transport (e.g., Leigh syndrome) which are associated with high rates of mortality. Indeed, the importance of balanced oxygen delivery and consumption to ensure normal metabolism (e.g., oxidative phosphorylation) and avoid oxidative stress is well established.
In certain circumstances it can be desirable to modulate (i.e., increase or decrease) the quantity of oxygen in a mammal, either systemically or locally (e.g., in an organ or portion thereof, tissue, cells). For example, appropriate modulation of oxygen levels can be therapeutically beneficial for individuals with anemia or oxidative stress, or in individuals to be treated by local oxygen starvation at the site of a tumor. Thus, a need exists for methods to modulate the concentration of oxygen in a mammal.
When macrophages are activated by bacteria, bacterial products, T lymphocyte-derived cytokines, and antigens, they respond by converting arginine into NO via nitric oxide synthase. Blocking the synthetic pathway of NO production has been demonstrated to alleviate immunologically mediated joint destruction that occurs in animal models of arthritis, as well as in glomerulonephritis (McCartney-Francis, N. et al., J. Exp. Med. 178:749–754 (1993); Weinberg, J. B. et al., J. Exp. Med. 179:651–660 (1994)). NO is also thought to play a role in other inflammatory conditions such as colitis, iritis and hemodynamic shock. In addition, tumor cells secrete NO to regulate blood flow. Thus, methods of therapy to reduce the concentration of NO are desirable to alleviate these conditions.